Novel PKD1 deletions and missense variants in a cohort of Hellenic polycystic kidney disease families

The autosomal dominant form of polycystic kidney disease is a very frequent genetically heterogeneous inherited condition affecting approximately 1 : 1000 individuals of the Caucasian population. The main symptom is the forma tion of fluid-filled cysts in the kidneys, which grow progressively in size and number with age, and leading to end-stage renal failure in approximate ly 50% of patients by age 60. About 85% of cases are caused by mutations in the PKD1 gene on chromosome 16p13.3, which encodes for polycystin-1, a mem branous glycoprotein with 4302 amino acids and multiple domains. Mutation d etection is still a challenge owing to various sequence characteristics tha t prevent easy PCR amplification and sequencing. Here we attempted a system atic screening of part of the duplicated region of the gene in a large coho rt of 53 Hellenic families with the use of single-strand conformation polym orphism analysis of exons 16-34. Our analysis revealed eight most probably disease causing mutations, five deletions and three single amino acid subst itutions, in the REJ domain of the protein. In one family, a 3-bp and an 8- bp deletion in exons 20 and 21 respectively, were co-inherited on the same PKD1 chromosome, causing disease in the mother and three sons. Interestingl y we did not find any termination codon defects, so common in the unique pa rt of the PKD1 gene. In the same cohort we identified 11 polymorphic sequen ce variants, four of which resulted in amino acid variations. This supports the notion that the PKD1 gene may be prone to mutagenesis, justifying the relatively high prevalence of polycystic kidney disease.